https://www.ncbi.nlm.nih.

gov/pmc/articles/P
MC4895196/

Salivary oxytocin in clinically anxious youth:

Associations with separation anxiety and
family accommodation
Eli R. Lebowitz,a,* James F. Leckman,a Ruth Feldman,b Orna Zagoory-Sharon,b Nicole
McDonald,a and Wendy K. Silvermana
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Abstract
Clinical anxiety disorders in youth are common and associated with interpersonal behaviors
including reliance on parents for family accommodation, or changes that parents make to their
own behaviors to help the youth avoid anxiety related distress. The neuropeptide oxytocin is
associated with the regulation of anxiety and of close interpersonal behavior leading to the
hypothesis that oxytocinergic functioning plays a role in youth anxiety and its disorders, and the
resulting family accommodation. To test this hypothesis salivary OT from 50 youth with primary
DSM-5 anxiety disorders was assayed. A multi-source/multi-method anxiety assessment
including semistructured interviews with youth and mothers, rating scales, and behavioral
observations was used to assess anxiety disorders and symptoms, and family accommodation.
Youth with separation anxiety disorder had significantly lower salivary OT levels than clinically
anxious youth not diagnosed with separation anxiety disorder. Salivary OT levels were
significantly negatively correlated with separation anxiety symptoms based on both youth- and
mother-ratings. Anxious behavior displayed by youth during interactions with their mothers was
associated with lower salivary OT levels in youth. Maternal ratings of family accommodation
were negatively associated with salivary OT levels in youth. Results support the role of the
oxytocinergic system in youth anxiety and its disorders and in parental involvement in youth
anxiety through family accommodation. OT may be particularly important for diagnoses and
symptoms of separation anxiety, which is inherently interpersonal in nature. Findings have
potentially important implications for assessment and treatment of anxiety in youth.
Keywords: Anxiety disorders, Oxytocin, Separation anxiety, Mother–child relations, Child,
Pituitary hormones, Posterior
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1. Introduction
Systems for threat detection and anxiety regulation overlap in the brain with systems for social
attachment and affiliative behavior, with shared neurochemistry and overlapping circuitry (see
MacDonald and Feifel, 2014 for a recent review). Social and attachment-related stimuli, as well
as danger and threat-related stimuli activate shared neural circuitry, signaling the hypothalamic
neuropeptide system, and producing behavioral responses of approach and avoidance,
respectively (Damsa et al., 2009; LeDoux, 2003; Paulus and Stein, 2006). In infancy and
childhood in particular, child–parent proximity and attachment behaviors provide a safety signal,
linking threat avoidance systems to attachment-related approach (Hofer, 1994; Porges, 2003).

Anxiety disorders in human youth are common (Costello et al., 2005; Messer and Beidel, 1994)
and characterized by interpersonal behaviors such as heavy reliance on parents for help in
regulating and avoiding feelings of anxiety, a process known as family accommodation (Benito
et al., 2015; Lebowitz et al., 2013; Thompson-Hollands et al., 2014). Family accommodation
helps to alleviate the anxious youth’s distress in the short term but can maintain youth anxiety
over time (Lebowitz et al., 2013; Peris et al., 2008). The neuropeptide oxytocin (OT) plays
important roles for both the regulation of anxiety and the modulation of close interpersonal
behaviors (Bethlehem et al., 2013; Carter, 2003; Feldman, 2015; Feldman et al., 2007;
MacDonald and Feifel, 2014; Rilling and Young, 2014), suggesting that OT may be implicated in
pediatric anxiety disorders and in family accommodation. Past work provides preliminary
research evidence for a link between OT and anxiety symptoms but the current study is the first
to examine peripheral OT levels in youth with anxiety disorders.

Carson et al. (2015) assayed cerebrospinal fluid (CSF) and plasma collected from ten youth (ages
6–18) who were undergoing CSF-related medical procedures (e.g., lumbar puncture) and
examined their respective associations with parents’ ratings of their children’s trait anxiety
symptoms. Youths’ OT levels in both CSF and plasma were significantly negatively associated
with the parents’ ratings. Other investigative groups have also found significant negative
correlations between anxiety symptoms and plasma OT levels in different segments of the adult
population including women with fibromyalgia (Anderberg and Uvnas-Moberg, 2000), clinically
depressed men and women (Scantamburlo et al., 2007), and nursing mothers (Stuebe et al.,
2013). Weisman et al. (2013) examined plasma OT levels in 473 non-clinical adults (41.5%
males), and found that males showed a significant negative correlation between plasma OT
levels and trait anxiety.

Research linking peripheral OT levels to anxiety symptoms has generally focused on global
symptom ratings (e.g., trait anxiety). Given OT’s role in interpersonal behavior it may be fruitful
to examine peripheral OT levels across different domains of youth anxiety and its disorders.
Separation anxiety in particular straddles the line between anxiety and close interpersonal
behavior, as separation from attachment figures is the primary trigger for the anxiety symptoms
(American Psychiatric Association, 2013). Parental involvement is also more inevitable in
separation anxiety disorder compared to other anxiety disorders, and youth and mothers report
particularly high levels of family accommodation in cases of separation anxiety disorder
(Lebowitz et al., 2014b, 2013). No studies have examined peripheral OT levels in youth or adults
with separation anxiety disorder, but one study by Eapen et al. (2014) found that ratings of
separation anxiety in 57 pregnant women were significantly negatively correlated with plasma
OT levels from the same women 3 months post-partum.

The current study is the first to investigate peripheral OT levels in youth anxiety and its
disorders, including family accommodation of the anxiety by mothers. The study used a multi-
source/multi-method anxiety assessment strategy, including semi-structured diagnostic
interviews, youth self-rating scales, mother-rating scales, and independent coded observer ratings
of youth anxious behavior, to examine overall symptom severity and specific diagnoses and
domains of anxiety.

The study hypotheses were that youth salivary OT levels would be negatively correlated with
severity of youth anxiety symptoms, as assessed through the multi-source/multi-method anxiety
assessment (Silverman and Ollendick, 2005). Youth salivary OT levels were also hypothesized to
be negatively correlated with the degree family accommodation, as rated by mothers and youth.
Higher levels of association were expected in youth with separation anxiety, compared to other
anxiety disorders and symptoms, because of the interpersonal nature of separation anxiety
disorder.

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2. Materials and methods

2.1. Participants

Participants were 50 clinically anxious youth aged 7–16 years (mean age = 11.86 years; SD =
3.19; 55% females) and their mothers, who presented consecutively to a large specialty anxiety
disorders research clinic. All youth met DSM-5 (American Psychiatric Association, 2013)
criteria for a primary anxiety disorder. The primary diagnoses included: generalized anxiety
disorder (GAD, 30%), social anxiety disorder (SoA, 28%), separation anxiety disorder (SAD,
22%), specific phobia (SP, 15%), and panic disorder (PD, 5%). Overall, including both primary
and non-primary diagnoses, 68% of youth had GAD (N = 34 aged 7–17), 65% had SoA (N = 32,
aged 7–17), 32% had SAD (N = 16, aged 7–15), 22% had SP (N = 11, aged 7–17), and 13% had
PD (N = 7, aged 13–17). Psychiatric medications taken by youth included a typical
antipsychotics (N = 3), antidepressants (N = 6), and stimulants (N = 1).

Non-anxiety disorder comorbid diagnoses included attention deficit hyperactivity disorder

(20.6%), major depression (10.3%), oppositional defiant disorder (5.9%), and conduct disorder
(1.5%). All participants were enrolled in a regular educational setting. English was the primary
language spoken in most (93.1%) of the homes with the remainder having Spanish as primary
language. Youth were predominantly White (83.3%) and non-Hispanic (94.5%), with a minority
being African American (6%), Asian (2%), or of mixed ethnic background.
The Institutional Review Board at the Yale University School of Medicine approved this study.
Upon arrival, study procedures were explained and signed informed consents and assents were
obtained from mothers and youth, respectively. Youth and mothers were then separately
administered a semi-structured diagnostic interview and rating scales. Youth provided a salivary
sample for analysis and then youth and mothers participated in a brief, four-minute dyadic
interaction during which they planned a ‘fun day’ together, which was videotaped for subsequent
behavioral coding. A second saliva sample was collected from the youth after the dyadic
interaction.

2.2. Assessment of youth anxiety and family accommodation

The presence of a primary DSM-5 anxiety disorder diagnosis was established using the Anxiety
Disorders Interview Schedule—Children and Parent (ADIS-C/P), administered separately to the
child and the mother (Silverman et al., 2001). Severity of youth anxiety symptoms was assessed
using respective youth and mother versions of the Multidimensional Anxiety Scale for Children
(MASC2), a 50-item rating scale for anxiety in youth that contains subscales for particular
domains of anxiety including: separation anxiety, social anxiety, physical symptoms, harm
avoidance, generalized anxiety, and obsessive–compulsive symptoms (March, 2013). MASC has
been shown to have good validity as a self-rated indicator of anxiety severity across the school
age (March, 1997) and several studies have confirmed the factorial structure of the MASC and
its ability to distinguish particular domains of anxiety (Baldwin and Dadds, 2007; Grills-
Taquechel et al., 2008; March et al., 1999). Family accommodation was assessed using
respective youth and mother versions of the Family Accommodation Scale Anxiety (FASA) that
includes a total accommodation score based on 9 items and subscales for participation in
symptom driven behavior (e.g., “How often did you assist your child in avoiding things that
might make him/her more anxious”), and modification of family routines and schedules (e.g.,
“Have you modified your work schedule because of your child’s anxiety”) (Lebowitz et al.,
2014b, 2013). The FASA also includes one additional item that assesses the degree to which the
accommodations are distressing to the parent, and three items relating to negative child reactions
to not being accommodated. Previous research demonstrated the validity of FASA a child-rated
indicator of family accommodation for children between the ages of 6–17 (Lebowitz et al.,
2015). Youth and mothers also participated in a brief videotaped interaction, which was
independently coded for overt anxious youth behaviors using the child anxiety scale from the
widely used Coding Interactive Behavior system (Feldman, 1998). Child anxiety was coded on a
scale from 1 to 5 based on the presence, frequency, and severity of overt anxious behaviors (e.g.,
nail biting, excessive fidgeting, verbal expression of current fear or anxiety). As in previous
research (Feldman, 2010), a uniform prompt was provided instructing the dyad to ‘plan their best
day together.’ Coders were trained to reliability and blind to all clinical information. Inter-rater
reliability was r = 0.79.

2.3. Sample preparation and immunoassay

Salivary OT provides an easy and non-invasive method of examining peripheral OT levels,

although the coordination between various peripheral measure remains an area of research
(Weisman et al., 2012). Earlier research has demonstrated the link between salivary and plasma
measures of OT (Feldman et al., 2011), and salivary OT is elevated after intranasal OT
administration (Weisman et al., 2012).

Saliva was collected using Salivettes (Sarstedt, Rommelsdorf, Germany). Saliva samples were
collected between 4PM and 6PM. Participants did not eat for 2 h and did not drink for 30 min,
prior to the saliva collection. Two samples were collected from each participating youth, 7 min
apart. Samples were stored at −20 °C until centrifuged twice, 2 days apart, at 4 °C at 1500 × g for
20 min. Liquid samples were kept at −80 °C, lyophilized for 10 days, and stored at −20 °C. On
the assay day, the dry samples were reconstituted in water and concentrated ×4 before
immunoassay.

In numerous past research studies we measured peripheral OT levels using an ELISA kit from
Assay Designs® (Feldman et al., 2010a, 2011, 2012; Gordon et al., 2008; Weisman et al., 2013).
That kit is no longer available (Assay Designs having been purchased by Enzo®). The Enzo®
(NY, USA) OT kit used in the current study is less sensitive to small concentrations of OT,
necessitating careful sample preparation with the following modifications relative to our
previous procedure: samples were centrifuged twice; delicate lyophilization maintaining constant
refrigeration to slow the drying; and reconstitution of the samples in water prior to assay. No
standard OT concentration values exist as yet for the new kit and caution must be exercised in
interpreting absolute values.

Measurements were performed in duplicate and the concentrations of samples were calculated
using Matlab-7 according to relevant standard curves. The intra-assay and inter-assay
coefficients of variability are less than 14.7%.

2.4. Statistical analysis

Study data were managed and analyzed using SPSS20. Comparison of mean salivary OT
concentrations across anxiety disorder diagnoses was determined using independent sample t-
tests, controlling for the multiple tests using Holms Bonferroni (Holm, 1979). Because of the
high comorbidity between anxiety disorders which is common in clinically anxious samples
(Costello et al., 2005; Walkup et al., 2008) t-tests compared those with and without each
disorder, regardless of whether the disorder was the primary diagnosis or a secondary anxiety
diagnosis.

Associations between salivary OT levels and parent and child ratings of overall anxiety and
MASC2 subscales for the various anxiety domains, as well as ratings of family accommodation
were determined using Pearson bivariate correlations. We also conducted a hierarchical linear
regression with salivary OT levels as the dependent variable to determine the relative
contribution of the various predictors including demographic variables, anxiety measures, and
family accommodation.

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3. Results
Table 1 presents clinical sample characterization, as well as relations between study variables.
Mother and youth ratings of youth anxiety and family accommodation were consistent with those
found in other clinical samples of anxious youth reflecting the clinical nature of the sample
(RUPP Anxiety Study Group, 2002). Salivary OT levels ranged from 6 pg/ml to 64 pg/ml with a
distribution that was not significantly different from normal (K–S test = 0.15, p > 0.05) though
with moderate positive skewness (1.2, SEM = 0.34) and kurtosis (1.4, SEM 0.68). Male and
female youth did not differ significantly on mean salivary OT levels or on any of the study
variables, and use of psychiatric medications was not associated with salivary oxytocin levels.
Child age was significantly positively correlated with child salivary OT levels (r48 = 0.40, p <
0.01). Salivary OT levels were measured twice, before and after a brief 4 min mother–youth
dyadic interaction, and the two samples were significantly positively correlated (r = 0.51, p <
0.001) and did not differ significantly. Six youth did not produce enough saliva for analysis the
second time due to dry mouth. Because of this, and because the mother–youth dyadic interaction
has potentially direct bearing on upward or downward regulation of the OT system, in particular
in the context of separation anxiety, we used the first measurement (before the dyadic
interaction) in the study analyses.

Table 1

Clinical characteristics of anxious youth (N = 50) and correlations with salivary oxytocin levels,
with significance and 95% confidence intervals.

Correlation with youth salivary

Mean SD oxytocin p (95% CI)
Youth salivary oxytocin 22.9 14.0 – –
(pg/ml)
Youth Anxiety: Mother-Report (MASCa)
 Total 62.6 22.6 −0.30* 0.04 (0.02–0.53)
 Separation 11.1 6.1 −0.40** 0.006 (0.14–
0.61)
 Generalized 15.4 5.3 −0.31* 0.03 (0.03–0.54)
 Social 15.9 6.3 −0.34* 0.02 (0.07–0.56)
 Obsessive–compulsive 5.7 6.3 −0.18 0.21
 Physical/somatic 10.7 6.6 −0.1 0.52
 Harm avoidance 16.5 4.0 −0.03 0.85
Youth Anxiety: Self-Report (MASCa)
 Total 71.4 26.9 −0.09 0.55
 Separation 11.5 5.5 −0.38** 0.009 (0.11–
0.59)
 Generalized 14.8 6.0 −0.12 0.41
 Social 14.1 7.1 0.04 0.77
 Obsessive–compulsive 12.1 6.9 −0.9 0.54
 Physical/somatic 14.6 8.1 0.03 0.83
 Harm avoidance 16.2 4.4 −0.06 0.69
 Correlation with youth salivary
Mean SD oxytocin p (95% CI)
Youth anxiety-behavioral 2.3 0.9 −0.45** 0.006 (0.20–
codingb 0.65)
Family Accommodation Mother-Report (FASAc)
 Total 15.6 8.2 −0.34 0.19 (0.07–0.56)
 Participation 10.5 4.9 −0.44 0.002 (0.18–
0.64)
 Modification 5.1 4.0 −0.17 0.26
 Distress 1.4 1.0 −0.12 0.44
 Consequences 4.9 3.6 −0.26 0.85
Family Accommodation Youth-Report (FASA-CRc)
 Total 11.4 7.0 −0.05 0.76
 Participation 8.3 4.7 0.04 0.78
 Modification 3.1 3.0 0.17 0.26
 Distress 1.1 1.2 −0.50** <0.001 (0.26–
0.68)
 Consequences 5.8 3.4 −0.33* 0.02 (0.06–0.56)
Open in a separate window
a
Multidimensional Anxiety Scale for Children.
b
Behavioral coding of youth anxiety during mother–youth dyadic interaction was on a scale of 1–
5.
c
Family Accommodation Scale Anxiety (Child Report).
*
p < 0.05.
**
p < 0.01.

3.1. Salivary oxytocin levels and youth anxiety symptoms

3.1.1. Group comparisons by anxiety disorder diagnosis

Youth with separation anxiety disorder had significantly lower mean salivary OT levels (16.7
pg/ml, SD = 7.6) than anxious youth not meeting criteria for separation anxiety disorder (26.8
pg/ml, SD = 15.6) (t48 = 2.61, p < 0.01). No other anxiety or non-anxiety diagnosis was
associated with significant differences in child salivary OT levels. Youth with separation anxiety
were predictably younger than anxious youth without separation anxiety (t = 2.9, p < 0.01) and
youth age was thus included as a predictor of youth salivary OT levels in the subsequent
multivariate regression model.

3.1.2. Youth self-rated anxiety

Salivary OT levels were significantly negatively correlated with child MASC2 ratings of
separation anxiety symptoms (r48 = −0.38, p < 0.01; 95% CI: 0.11–0.59; partial correlation
controlling for age: rpartial = −0.30, p < 0.05), but not significantly associated with other domains
of youth self-rated anxiety or total MASC scores (see Fig. 1).
Fig. 1

Youth ratings of youth separation anxiety, and youth salivary oxytocin levels (N = 50).

3.1.3. Mother-rated youth anxiety

Child salivary OT levels were significantly negatively associated with overall child anxiety and
several indices of anxiety domains (separation anxiety; generalized anxiety; social anxiety).
However, after correcting for the multiple correlations, only separation anxiety scores were
significantly associated with youth salivary OT levels (r48 = −0.40, p < 0.01; 95% CI: 0.14–0.61;
partial correlation controlling for age: rpartial = −0.29, p < 0.05; see Fig. 2).
Fig. 2

Mother ratings of youth separation anxiety, and youth salivary oxytocin levels (N = 50).

3.1.4. Coded behavioral observation of child anxiety

Child anxiety, as coded by independent blinded raters, was significantly negatively associated
with child salivary OT levels (r48 = −0.447, p < 0.01; 95% CI: 0.20–0.65; partial correlation
controlling for youth age rpartial = −0.37, p < 0.05). Table 1 summarizes the association between
youth’s salivary OT levels and the various clinical measures.

3.2. Salivary oxytocin levels and family accommodation of child anxiety

3.2.1. Mother-rated family accommodation

Youth salivary OT levels were significantly negatively associated with overall level of mother-
rated family accommodation on FASA (r48 = −0.34, p < 0.05; 95% CI: 0.07–0.56) and the
participation subscale of FASA (r48 = −0.44, p < 0.01; 95% CI: 0.18–0.64). Youth salivary OT
levels were not significantly associated with maternal ratings of distress associated with the
accommodation or with negative youth consequences if not accommodated. Total mother-rated
FASA scores were negative associated with youth age (r48 = −0.30, p < 0.05).

3.2.2. Youth-rated family accommodation

Youth salivary OT levels were significantly negatively associated with youth’s ratings of
negative consequences such as becoming distressed or anxious when not accommodated (r48 =
−0.33, p < 0.05; 95% CI: 0.06–0.56), but was not significantly associated with youth-ratings of
family accommodation levels.

3.3. Hierarchical multiple regression

We conducted hierarchical linear multiple regression to examine the relative contributions of the
three families of variables found to be correlated with child salivary OT levels: child
demographic variables (age), child level variables (anxiety indices), and interpersonal or family-
level variables (accommodation indices). Including child age in the multiple regression allowed
us to examine the effect of the other variables above and beyond the relation between child
salivary OT levels and child age. Youth salivary OT level was the dependent variable. Variables
were entered in the equation in three blocks. Youth age was entered first as the predicting
variable. Next the three anxiety measures that were most significantly related to child salivary
OT levels were entered into the equation: child-rated separation anxiety subscale of MASC2,
mother-rated separation anxiety subscale of MASC2, and one dummy variable coded to reflect
meeting or not meeting criteria for SAD based on the clinician administered ADIS. Finally, in a
third block we included the two family accommodation indices that correlated with child salivary
OT levels: mother-rated participation subscale of FASA, and child-rated negative consequences
of not being accommodated. Collinearity between all variables was acceptable (VIF < 1.5 and
tolerance below 1.0 for all variables). The overall regression model was significant (F = 5.74, p <
0.01) and explained 36.5% of the variance in child salivary OT levels (adjusted R2 = 0.30). Each
step in the model significantly increased the explanatory power of the regression. The first
equation, including only child age, yielded R2 of 0.16 (F = 8.49, p < 0.01). Adding the separation
anxiety measures, significantly increased the R2 to 0.24 (FChange = 4.20, p < 0.05). Adding the
family accommodation scores, further significantly increased the R2 to 0.36 (FChange = 3.90, p <
0.05). Table 2 summarizes the final third-step regression model.

Table 2

Unstandardized and standardized values from final step in hierarchical multiple regression model
predicting salivary oxytocin in clinically anxious youth (N = 50) from youth age, separation
anxiety, and family accommodation (R = 0.365, Adjusted R2 = 0.30, F = 5.74, p < 0.01).

Independent variable B SE BETA

Youth age 1.14 0.69 0.24
Child rated separation anxiety (MASC2) −0.39 0.40 −0.15
Mother-rated separation anxiety (MASC2) 0.20 0.41 0.10
Presence of separation anxiety disorder (ADIS C/P) −3.62 4.80 −0.12
Independent variable B SE BETA
Mother-rated family accommodation (FASA participation subscale) −0.84 0.44 −0.30
Child-rated consequences of not being accommodated (FASA) −1.1 0.60 −0.25

Note: MASC2 = Multidimensional Anxiety Scale for Children; ADIS C/P = Anxiety Disorders
Interview Schedule for Children, Child and Parent Versions; FASA = Family Accommodation
Scale Anxiety.

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4. Discussion
To our knowledge, this is the first investigation of oxytocinergic functioning in youth with
anxiety disorders. Convergent evidence from a multi-method/multi-source anxiety assessment
supports the role of OT in two key areas of youth anxiety that involve close interpersonal
behavior: separation anxiety and family accommodation.

Youth with separation anxiety disorder had lower salivary OT levels than youth not meeting
criteria for separation anxiety disorder. Likewise, using a dimensional approach, elevated
separation anxiety based on both youth and mother ratings, was associated with lower youth
salivary OT levels. Anxious behavior displayed by youth during interactions with their mothers
was also associated with lower youth salivary OT levels.

Another key interpersonal feature of youth anxiety that was associated with youth salivary OT
levels was family accommodation, or the degree to which mothers were involved in helping the
youth to avoid distress related to the anxiety symptoms. Mothers of youth with lower salivary
OT levels reported higher levels of family accommodation, suggesting that lower OT levels in
youth are associated with greater reliance on primary attachment figures for the regulation or
avoidance of internal distress and anxiety. Youth self-ratings indicated that greater distress at not
being accommodated was associated with lower youth salivary OT levels, further supporting the
link between OT and reliance on parents for accommodation in anxious youth.

Evidence of a complex role for the oxytocinergic system in the regulation of distress and the
modulation of close interpersonal behavior in humans as well as other mammals has been
mounting for several years (Carter, 2003; Feldman, 2015; Feldman et al., 2007; MacDonald and
Feifel, 2014). But the current report is the first to examine salivary OT levels in clinically
diagnosed youth with anxiety disorders, and opens up exciting new directions in this line of
research. Human anxiety symptoms are frequently conceptualized as having their roots in highly
conserved mammalian ‘defense systems’ which overlap with systems for social signaling,
attachment and bonding (Belzung and Philippot, 2007; Feldman et al., 2013; MacDonald and
Feifel, 2014). Pediatric anxiety rests at this overlap, as fear and distress in young mammals
activate the attachment system and are regulated interpersonally through the provision of
protective and soothing behaviors by caregivers. Separation anxiety disorder exemplifies this, as
separation from the primary attachment figure is the key trigger for the anxiety symptoms and
the presence of the attachment figure is the main means of reducing or avoiding the anxiety. The
specific associations between separation anxiety and salivary OT levels in the current data
underscore the interplay between systems for anxious arousal and systems for social signaling
and attachment.

Further research is crucially needed to advance understanding of the causal chains linking lower
salivary OT levels to separation anxiety disorder. Factors affecting the attachment system, such
as early rearing environment and parental psychopathology, may contribute to reduced or
disrupted functioning of the oxytocinergic system and to greater anxiety about separation from
attachment figures (Carter et al., 2001; De Wolff and van Ijzendoorn, 1997; van, 1995). Insecure
maternal attachment has been found to predict childhood anxiety and insecure attachment in
children, which can manifest as separation anxiety (Colonnesi et al., 2011; Manassis et al.,
1994). Data linking early adversity to lower peripheral OT levels in adulthood may support this
hypothesis (Opacka-Juffry and Mohiyeddini, 2012).

It is also possible that lower salivary OT levels signal more reliance on caregivers and more
attachment-oriented responses to anxiety in general. Rather than separation being the trigger for
the anxiety, the links between OT, separation anxiety, and family accommodation may reflect
how anxiety is managed (i.e., through parental proximity and family accommodation) rather than
what triggers it.

Parental variables may also be implicated in shaping offspring’s oxytocinergic functioning and in
contributing to, or maintaining, symptoms of childhood anxiety. Parental peripheral OT has been
linked to parenting behavior, which in turn has been shown to influence the oxytocinergic system
of infants, (Apter-Levy et al., 2013; Feldman et al., 2010b) and family accommodation has been
found to mediate the link between anxiety in mothers and youth (Jones et al., 2015).

Further research is also needed to understand more fully the neurobiological determinants of the
levels of OT measured in saliva. Although salivary OT level has been widely used as a potential
biomarker in human studies for a range of social behaviors for nearly a decade (Carter et al.,
2007), questions remain concerning the extent to which salivary OT is reflective of central or
even plasma levels of OT. It is well known that OT can be released in a coordinated fashion,
within the brain and from the posterior pituitary (Neumann and Landgraf, 2012). As a
consequence, it is not unexpected that OT has broad and synchronized behavioral and
physiological consequences. Conceptualizations suggesting coordination between central and
peripheral OT (Ross and Young, 2009) are supported by several lines of research including
associations between peripheral OT levels and allelic variability on the OXTR gene (Apter-Levy
et al., 2013; Feldman et al., 2012), and increased salivary OT levels up to seven hours after
intranasal OT administration (van Ijzendoorn et al., 2012; Weisman et al., 2012) which is thought
to have central effects (Burri et al., 2008), though this remains contested. A recent study of
intranasal administration in rats and mice indicated that it reached behaviorally relevant areas of
the brain, including the amygdala, with a parallel change in plasma OT levels (Neumann et al.,
2013). Significant associations between plasma and salivary OT levels (Feldman et al., 2010a,
2011; Hoffman et al., 2012) have also been reported but this has not been a universal finding
(Javor et al., 2014). While methodological considerations may well account for these discrepant
findings, the nature of the links between central and salivary OT release are not fully understood
and require further investigation. We speculate, however, that the innervation of the salivary
glands by the autonomic nervous system and the engagement of the autonomic nervous system in
mediating stress response in animal models may play an important role (Grippo et al., 2012;
Neumann and Landgraf, 2012; Quintana et al., 2013).

The link between oxytocinergic functioning, separation anxiety, and family accommodation
suggests novel directions for the treatment of anxiety in youth. Recently, treatments have been
developed that target the reduction of family accommodation as a means of treating anxiety in
youth (Lebowitz, 2013; Lebowitz et al., 2014a; Thompson-Hollands et al., 2014). The current
results support the biological modulation of family accommodation and suggest that peripheral
OT measurement may help to identify cases where a focus on family accommodation may be
particularly valuable. Lower salivary OT levels were associated with greater resistance on the
part of the youth to parental non-accommodation, suggesting the need for more intensive parent
training to cope with the ensuing difficulties. High family accommodation has been associated
with poorer treatment outcomes in OCD, (Garcia et al., 2010) and clinical experience suggests
this is the case in anxiety disorders as well. Research is needed to determine whether peripheral
OT level can be a useful predictor or moderator of treatment outcomes. Another intriguing
potential clinical implication is the possibility of intranasal OT administration as a treatment for
separation anxiety in youth. Studies have preliminarily examined the potential efficacy of
intranasal OT for anxiety disorders, with mixed results, but have not yet focused on youth or on
separation anxiety disorder (Feifel, 2011; Guastella et al., 2009; MacDonald and Feifel, 2012).
OT administration is also being explored as a possible treatment for other disorders characterized
by abnormal interpersonal behavior, such as autism (Andari et al., 2010). Replication of the
current results would suggest the possibility of exploring OT administration as an independent or
adjunct treatment strategy for youth with separation anxiety, particularly in cases of high family
accommodation.

In addition to our incomplete understanding of the determinants of salivary OT release (see

above), the current results must be interpreted in light of certain additional limitations. First, the
current study was not powered to examine the impact of comorbid nonanxiety disorders on
salivary OT levels. The presence of comorbid disorders was not associated with significant
differences in salivary OT levels in the current sample, but it is not possible to rule out potential
interactions between anxiety and other disorders in relation to salivary OT levels. Relatedly, a
larger sample would allow a more comprehensive examination of the various anxiety disorders,
using a multifactorial model rather than the t-tests based on the presence of individual diagnoses
included in the current study. The current results did not show a relation between gender and OT
levels, but previous research has suggested divergent roles for peripheral OT in anxiety in males
compared to females and a larger sample would allow for a fuller examination of this question
(Domes et al., 2010; Kubzansky et al., 2012; Weisman et al., 2013). Second, focusing on
clinically anxious youth with well-characterized symptomatology is strength of this study but
additional research is necessary to determine whether or not similar patterns of associations exist
in the non-clinical populations. The absence of a control comparison group is therefore a
meaningful and important limitation. Third, the current study focused on anxious children and
their mothers, as the role of mothers has been more thoroughly explored in child anxiety and in
family accommodation. However, paternal variables including the presence, anxiety,
accommodation, and oxytocinergic functioning of fathers also need to be explored, particularly
in light of some evidence for the role of fathers in shaping or preventing child anxiety (Bogels
and Phares, 2008). Fourth, in light of the evidence for multi-generational and possibly epigenetic
influences on the development of the oxytocinergic system (Apter-Levy et al., 2013; Feldman et
al., 2013; Kappeler and Meaney, 2010; Rilling, 2009) research is needed on the interplay
between maternal oxytocinergic functioning, maternal care, and child salivary OT levels and
anxiety symptoms. Such research is currently underway in our laboratory. Longitudinal research
would also be invaluable in ascertaining the causal chains linking lower peripheral OT levels to
the development and accommodation of childhood anxiety symptoms, in particular separation
anxiety.

Go to:

5. Conclusions
Salivary OT levels are negatively associated with anxiety symptoms in clinically anxious youth
and specifically associated with two interpersonal domains of youth anxiety: separation anxiety
and family accommodation, or parental involvement in the youth’s anxiety symptoms.

Go to:

Acknowledgments
Funding

Financial support for this research came from the NIMH grant K23MH103555 to Dr. Lebowitz,
and from a NARSAD Young Investigator Award (#21470) to Dr Lebowitz.

The funding sources were not involved in study design; in the collection, analysis and
interpretation of data; in the writing of the report; and in the decision to submit the article for
publication.

Support for this research came from the NIMH grant K23MH103555 to Dr. Lebowitz, and from
a NARSAD Young Investigator Award (#21470) to Dr Lebowitz. The authors gratefully
recognize the assistance of Ms. Krista Basile, Ms. Jelena MacLeod, and Ms. Alyssa Martino.

Go to:

Footnotes
Contributors

Dr. Lebowitz had the idea for the study, collected the biological specimens and behavioral data,
analyzed the data, and together with other authors prepared the manuscript.

Dr. Leckman contributed to the study conceptualization and planning, and to biological specimen
collection and analysis, and contributed to manuscript preparation.
Dr. Feldman helped with study planning and methodological considerations, provided training
and oversight for behavioral data analysis and for immunoassay, and contributed to manuscript
preparation.

Dr. Zagoory-Sharon handled specimen preparation, conducted the immunoassay and was
responsible for oxytocin quantification, and contributed to manuscript preparation.

Dr. McDonald contributed to analysis of behavioral data and to manuscript preparation.

Dr. Silverman contributed to study conceptualization and planning, and provided oversight of
clinical assessment and characterization, and contributed to data analysis and manuscript
preparation.

Conflict of interest

Dr. Lebowitz receives royalties from John Wiley and Sons, and Vandenhoeck & Ruprecht and
research support from the National Institutes of Health and the Brain and Behavior Research
Foundation. Dr. Leckman receives royalties from John Wiley and Sons, McGraw Hill, and
Oxford University Press and research funding from the National Institutes of Health. Dr.
Feldman receives research funding from the Simms–Mann Foundation and the Harris
Foundation and the German–Israeli Foundation, and the US–Israel Bi-National Science
Foundation. Dr. Silverman receives funding from National Institutes of Health. Drs. McDonald
and Zagoory-Sharon have no financial interests to disclose.

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